The potential role of precision medicine to alleviate racial disparities in prostate, bladder and renal urological cancer care

Abstract Background Racial disparities in oncological outcomes resulting from differences in social determinants of health (SDOH) and tumour biology are well described in prostate cancer (PCa) but similar inequities exist in bladder (BCa) and renal cancers (RCCs). Precision medicine (PM) aims to provide personalized treatment based on individual patient characteristics and has the potential to reduce these inequities in GU cancers. Objective This article aims to review the current evidence outlining racial disparities in GU cancers and explore studies demonstrating improved oncological outcomes when PM is applied to racially diverse patient populations. Evidence acquisition Evidence was obtained from Pubmed and Web of Science using keywords prostate, bladder and renal cancer, racial disparity and precision medicine. Because limited studies were found, preferred reporting items for systematic reviews and meta‐analyses (PRISMA) guidelines were not applied but rather related articles were studied to explore existing debates, identify the current status and speculate on future applications. Results Evidence suggests addressing SDOH for PCa can reverse racial inequities in oncological outcomes but differences in incidence remain. Similar disparities in BCa and RCC are seen, and it would be reasonable to suggest achieving parity in SDOH for all races would do the same. Research applying a PM approach to different ethnicities is lacking although in African Americans (AAs) with metastatic castrate‐resistant prostate cancer (mCRPCa) better outcomes have been shown with androgen receptor inhibitors, radium‐223 and sipuleucel. Exploiting the abscopal effect with targeted radiation therapy (RT) and immunotherapy has promise but requires further study, as does defining actionable mutations in specific patient groups to tailor treatments as appropriate. Conclusion For all GU cancers, the historical underrepresentation of ethnic minorities in clinical trials still exists and there is an urgent need for recruitment strategies to address this. PM is a promising development with the potential to reduce inequities in GU cancers, however, both improved understanding of race‐specific tumour biology, and enhanced recruitment of minority populations into clinical trials are required. Without this, the benefits of PM will be limited.

inequities in GU cancers, however, both improved understanding of race-specific tumour biology, and enhanced recruitment of minority populations into clinical trials are required.Without this, the benefits of PM will be limited.

K E Y W O R D S
genito-urinary cancers, precision medicine, racial disparity, social determinants of health, trial recruitment, tumour biology

| INTRODUCTION
According to CDC statistics, in the United States, over 300 000 urological cancers have been diagnosed each year since 2013, and 1 in 3 cancers in all men are urological in origin.Prostate cancer (PCa) was the most common in all racial groups as well as having the highest overall incidence in non-Hispanic Black men, whereas bladder (BCa) and renal cancers (RCC) are the second and third most common cancers, respectively, in Asian, Pacific Islander and non-Hispanic White (NHW) men. 1 With these figures in mind, there are concerning and significant ethnic and racial disparities in quality of care and treatment outcomes for all GU cancers.Several factors contribute to these inequities, including unequal access to care, poor clinical trial recruitment, socioeconomic and cultural factors in the generation of treatment plans and ethnic differences in tumour biology.In recent years, precision medicine (PM) has emerged as a promising approach to cancer care, aiming to provide individualized treatment to patients based on the genetic and molecular characteristics of their tumours.This paper will explore the potential role of PM in addressing racial disparities in GU cancers and discuss its implications for improving patient outcomes.

| RACIAL DISPARITIES IN GENITOURINARY CANCERS
(See Figure 1 illustrating factors influencing oncological outcomes in ethnic minorities, and the potential benefit of a PM approach).

| Epidemiology
Nearly 1 in 5 men in America will be diagnosed with PCa in their lifetime.Black men are 60% more likely than White men to be diagnosed with PCa and are 200% more likely than White men to die of the disease.In the United States, the lifetime risk for African American (AA) men of dying from PCa is twice that of NHW men.Hispanic men have increased odds of high-risk localized PCa than White men but are less likely to receive treatment.By contrast, Hispanic Black men are less likely to have high-risk localized disease than non-Hispanic Black men but are more likely to receive treatment. 2 These racial disparities are believed to result from differences in social determinants of health (SDOH) (for example, lifestyle and diet, social and cultural networks, healthcare access issues and comorbidities) and tumour biology.

| Lifestyle factors
Diet, obesity and lifestyle are increasingly regarded as important factors in PCa incidence and treatment outcomes, although there is a paucity of research relating these factors to race.Epidemiological study shows men migrating to the West, with long-term exposure to a Western diet (including fat, red meat, alcohol and dairy products), may increase the risk of PCa.However, studies focused on specific food items in western AA populations such as processed meats, poultry, fatty acids or plant-based foods have been inconclusive. 3Obesity has been linked to PCa risk and disease progression 4 and although AA men have a higher prevalence of obesity than Caucasian (CA) men, the difference is small. 5Nevertheless, a retrospective analysis of obesity as a predictor of adverse outcomes found it was linked to aggressive PCa in both AA and CA populations. 6

| Healthcare access
Relatively recently, two landmark epidemiological studies found once socioeconomic issues were equalized, differences in treatment outcomes were eradicated.One examined 306 100 patients with localized or locally advanced PCa from Surveillance, Epidemiology and End Results (SEER), Veterans Affairs (VA) Health System, and four pooled National Cancer Institute Radiation Therapy Oncology Group phase 3 randomized controlled trial databases, over 55 482 (18.1%) of whom were AA men, and the other a cohort of 60 035 PCa patients from the VA Health System, 30.3% of whom were AA.Once treatment was standardized and healthcare access issues resolved, stage for stage PCa mortality in AA men was not significantly different from NHW men in both studies. 7,8Another SEER study found that AA men with localized PCa were significantly less likely to receive definitive therapy compared with NHW men, regardless of tumour grade or risk group.Hispanic men with intermediate or high-risk diseases were also less likely to receive definitive treatment. 9A subsequent metanalysis evaluating the impact of SDOH on PCa outcomes in Black and White patients studied over 1 million patients from 47 studies and confirmed a significant link between race, SDOH and PCa outcomes, and reiterated the importance of addressing SDOH to achieve equitable treatment outcomes.cancer drug approvals from 2008 to 2018 reported just 3.1% of enrolled patients were Black; worse, the proportion of enrolled Black patients had declined from 3.6% to 2.9% over the decade.Hispanic enrollment is also underrepresented, making up just 6.1% of the enrolled patient population over the examined decade.Several issues must be overcome to improve trial recruitment for minority populations including eligibility criteria ruling out minorities with certain comorbidities, institutional locations that may favour more affluent populations, insurance problems and travel costs.There is a paucity of research into developing recruitment strategies to overcome these problems although one recurring theme is the importance of trust between minority communities and research institutions, as well as identifying leading community advocates to facilitate communication and understanding. 3

| Tumour biology
Although PCa genetic risk may be offset with a healthy lifestyle across all ethnic groups, 13 there is also evidence Black, Hispanic American (HA) and White populations may have fundamental differences in PCa tumour biology that influence a 'precision' treatment approach.In one of the largest comparative studies on this topic, data from a cohort of 1152 men (596 AA and 556 NHW) undergoing surgery for localized PCa at a single centre by a single surgeon were examined retrospectively. 14On post-surgical pathology specimens, AA men had significantly higher genomic scores for low-risk Gleason grade groups (GGGs) (GGG 1 and 2), whereas NHW men had significantly higher genomic scores for high-risk GGGs (GGG 4 and 5 Examining molecular pathway activity for pathways implicated in PCa development and progression, NHW men have increased activity in DNA repair, fatty acid and glycolytic metabolism and WNT/betacatenin gene signalling, whereas AA men have higher activity in immune response, hypoxia, reactive oxygen and apoptosis-related genes.Based on their increased expression of inflammatory genes, their findings advocate the use of immunotherapy in AA men, which supports the findings of a subanalysis of the Provenge Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED) trial demonstrating a survival advantage in AA men with metastatic castrate-resistant prostate cancer (mCRPCa) treated with sipuleucel-T. 14Other studies examining tumour mutations by race have shown Black men have higher mutation frequency in actionable genes (e.g.epidermal growth factor receptor [EGFR], v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 [ERBB2], breast cancer gene 1/2 [BRCA1/2] and phosphatidylinositol-4,-5-bisphosphate 3-kinase [PIK3CA]) in primary and metastatic PCa and in androgen receptor and DNA repair genes in metastatic PCa compared with White and Asian men. 15,16Using genomic analysis of tumour tissue to plan PM has promise, but once again incorporating genomic analysis into clinical trials has been highly Eurocentric.As research in genomic prognostic models expands, it is crucial that the data from which these algorithms are developed includes minority populations, or even better, prognostic models are developed that are themselves ethnic-specific.

| Epidemiology
Black race has been found to be an independent predictor of delayed diagnoses and treatment for BCa and inferior quality of care. 17,18A National Cancer Database (NCDB) study of BCa found AA patients have a higher proportion of muscle invasive bladder cancer (MIBC) and higher grade disease. 19A SEER database study showed Black patients were significantly less likely to undergo radical cystectomy (RC), which is strongly associated with overall survival, and another analysis from the NCDB reported that Black patients with MIBC undergoing RC were less likely to undergo pelvic lymph node dissections (PLNDs) and among those who underwent PLND, fewer lymph nodes were removed, both of which have been associated with improved outcomes. 17,20Similarly AA race is independently associated with a higher risk of recurrence post RC and worse overall survival for metastatic disease. 21,22SEER study collecting data from the 1970s to 1990s found a disproportionately higher rate of delayed diagnosis and treatment among AAs for BCa, and despite a recognition of these disparities, more contemporary real-world data from the last two decades has shown no improvement.In fact, the most recent NCDB analysis revealed, except for uninsured patients, Black race was the strongest independent predictor of BCa diagnosis at a later stage, and this discrepancy only widened as the stage advanced.23

| Tumour biology
An understanding of any differences in tumour biology is crucial to PM initiatives.Regardless of ethnicity, current PM bladder cancer research has focused on personalizing treatment based on P53 status, fibroblast growth factor (FGFR) expression and alterations, human epidermal growth factor receptor (HER) targeting, PIK3CA alterations, mutations in DNA damage response and repair genes and BCa molecular subtypes. 24However, any racial differences based on the above proposed categories for personalized therapies or the differences in higher grade disease in AA populations found in the NCDB study are poorly understood.Studies focused on identifying specific genomic subtypes of bladder cancer unique to AA patients have found, for example, EGF containing fibrulin-like extracellular matrix protein 1 (EFEMP1), S100 calcium binding protein A16 (S100Ar16), and myeloid cell leukemia 1 (MCL1) may be overexpressed in AA patients. 25EMP1 overexpression is a plausible mechanism contributing to muscle invasion and elevated S100A16 protein has been shown to inhibit apoptosis via the alpha serine/threonine-protein kinase/Bcell lymphoma 2 (AKT/Bcl-2) pathway in mitomycin C (MMC) resistant cell lines, whereas suppression of S100A16 may restore MMC sensitivity. 26MCL1 is an anti-apoptotic protein of the B-cell lymphoma 2 (BCL2) family and its downregulation is linked to tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) sensitization such that therapeutic MCL1 inhibition may potentially enhance the effect of Bacillus Calmette-Guerin (BCG) in non-MIBC. 25e same study also found an aggressive genetic subtype, known as C3, is associated with a worse response to surgery and a better response to immune checkpoint inhibitors.Given that AA patients have reduced transcription levels of the genes associated with this aggressive C3 subtype, they may have better outcomes with surgical treatment as opposed to immune checkpoint inhibitors. 25,273 | Renal cancer

| Epidemiology
RCC has an incidence of 2%-3% per year which is rising. 28Although RCC research in minority populations is generally lacking, AA, Native American (NA) and HA men have an increased risk of RCC, 29,30 and NAs and HAs are more likely to be diagnosed at a younger age.AA men have a higher incidence of localized disease at diagnosis although studies indicate AA men have increased mortality compared with age and stage-matched controls. 31Another study came to the same conclusion in a cohort of patients from the International Marker Consortium for RCC database which showed AA patients who recur had an increased risk of cancer-specific death and that the cause of this is likely multifactorial resulting from both SDOH and differences in tumour biology. 32

| Tumour biology
RCC classification is closely linked to its tumour biology and as our understanding of RCC molecular biology has improved, molecular subtypes have been added, including the most recent WHO classification in 2022. 33As well as the histologically defined RCCs (clear cell, papillary, oncocytic and chromophobe, collecting duct and histological variants), there are now 11 categories of molecularly defined renal cancers, for example, TFE3-rearranged RCC, TFEBaltered RCC, ELOC (formerly TCEB1)-mutated RCC, fumarate hydratase-deficient RCC, succinate dehydrogenase-deficient RCC, ALK-rearranged RCC and three categories of SWI/SNF-related matric associated actin-dependent regulator of chromatic subfamily Similarly, in recent years, RCC driver mutations have been investigated, most notably, the loss of heterozygosity of the von Hippel-Lindau (VHL) suppressor gene.This has led to the development of therapeutic targets for the vascular endothelial growth factor (VEGF) pathway with drugs such as Pazopanib and Sunitinib, providing viable alternatives to the mammalian target of rapamycin (mTOR) targeting agents. 34Subsequently genomic studies have shown intrinsic differences in RCC between AA and White patients, focusing specifically on the nine most common mutations: VHL, protein polybromo-1 human (PBRM1), SET domain containing 2 (SETD2), lysine-specific demethylase 5C (KDM5C), phosphatase and tensin homolog (PTEN), BRCA1-associated protein 1 (BAP1), mTOR, tumor protein p53 (TP53) and phosphoinositide 3-kinase (PI3KC).Finding, for example, AAs have less frequent VHL mutations suggesting VEGF targeted therapy may be less efficacious.

On the basis of an additional classification of clear cell RCC into
CC-e.1, CC-e.2 and CC-e.3,where 'e' stands for 'enriched' on genomic analysis with clustering on a heat map, 35 the same study found AAs have a higher frequency of CC-e.3 subtype compared with EAs, less PBRM1 mutations in those AAs with CC-e.1 and CC-e.2 subtypes compared with EAs and higher frequency of BAP1 mutations in those AAs with CC-e.3 subtype compared with EAs. 36By contrast, the frequencies of different molecular subtypes in HAs and NAs remain poorly investigated, despite, for example, HAs and NAs having a higher incidence of RCC along the US-Mexico border, as well as a higher prevalence of risk factors such as chronic renal disease and obesity. 30The use of PM is unlikely to be available for these populations until such time as their recruitment to clinical trials is improved.

| PRECISION MEDICINE AND ITS POTENTIAL BENEFITS IN ALLEVIATING RACIAL DISPARITIES
(See Table 1 listing current GU cancer clinical trials focused on PM with illustration of their inclusion of racial diversification in recruitment or outcomes and Figure 1 illustrating factors influencing oncological outcomes in ethnic minorities, and the potential benefit of a PM approach).
An early definition of PM took into consideration various patient characteristics, including age, family history and performance status, but has now expanded to include molecular, pathological, lifestyle or genomic factors when available. 37The future vision for PM aims to include integrated 'omics' data which may reveal insights into tumour biology through study not only of genomics but also transcriptomics, proteomics, metabolomics, immune pathways and the microbiome.
Our increasing understanding of these cellular pathways and their mechanistic links to the pathogenesis of cancer has led to the creation of many targeted systemic agents for a variety of cancers, including GU cancers. 38,39 A B L E 1 GU clinical trials focused on precision medicine in GU cancers.

| PTEN-Pl3K-AKT pathway inhibitors
For example, increasingly these medications are employed earlier in the disease course making castrate resistance more likely to develop, 40,41 and mutations in the PTEN-PI3K-AKT pathway are often seen in mCRPCa. 42In an analysis of castrate-resistant patients treated with abiraterone after docetaxel, patients with PTEN mutations experienced worse overall survival (OS).Further studies, including the randomized phase III IPATential150 trial, may more clearly define the role of AKT inhibitors but, as the authors have found is a common problem in PM research, the protocol does not seem to include active recruitment for racially diverse patients. 43,44Table 2 summarizes the trials found in the literature focused on mCRPC with cohorts including AA men.

| Antiandrogen agents
Trials using the novel oral antiandrogen abiraterone in a prospective cohort of prechemotherapy mCRPCa patients demonstrated an enhanced PSA response in Black men (greater than 90% drop in PSA in over 50% of patients compared with only 30% of White patients), 45 as did a similar study with equitable access for Black men with nearly 70% of Black men halving their PSA compared with 49% of White men. 46Survival rates for Black men with mCRPCa are similarly more favourable than for White men treated with novel oral antiandrogens, with studies showing 918 versus 781 days OS, respectively, using either enzalutamide or abiraterone 47 and 16.6 versus 11.5 months PSA progression free survival, respectively, with abiraterone. 48More recently, early results from the PANTHER trial, suggest Black men with mCRPCa also have a better response to combined abiraterone and apalutamide [an AR receptor inhibitor] with prednisolone than White men. 49The efficacy of these treatments in other racial groups requires further study.

| Autologous cellular immunotherapy
In general, immunotherapies have been less successful in PCa with the notable exception of the Sipuleucel-T vaccine.1][52]

| Checkpoint inhibitors
These results are consistent with other studies that suggest that AAs with PCa exhibit a more pronounced upregulation of immune signalling pathways. 54As discussed above, several genes involved in inflammatory pathways and immune checkpoint inhibition (ICI), such as IFN-G, CCL4 and IL33, and immune biomarkers, including CD3, ICOSLG and PDL2, are expressed at significantly higher levels in tumours from AAs, 14 which may underlie their improved efficacy with carefully chosen chemo-and immuno-therapy regimes.A large metanalysis also found improved survival in Black men with mCRPCa with Docetaxel on multivariable analysis pooling 9 phase 3 trials with nearly 9000 men, 500 of whom were Black. 55

| Abscopal effect
Lastly, there has been increased interest in combining immunotherapies with radiation therapy (RT) to utilize 'the abscopal effect' resulting from RT-induced immune activation and upregulation of inflammatory chemokines resulting in tissue-and tumour-infiltration by antigen-presenting and cytotoxic lymphocytes to reduce disease burden at distant sites. 56,57Immunotherapy may then leverage the immune system via a myriad of mechanisms, including anti-tumour vaccination and ICI to prevent the apoptosis of cytotoxic T-cells. 58,59[62] In clinical settings, stereotactic body radiation therapy (SBRT) has been used to trigger antitumour immunity in patients on immunotherapy based on the rationale that combining these treatment modalities may increase their collective efficacy as they both reduce regulatory T cells and increase tumour infiltration by lymphocytes. 63A recent study combined SBRT and immunotherapy in men with mCRPC with at least one bone metastasis who had progressed after receiving docetaxel.The subjects were randomized in a 1:1 ratio to receive bone-directed RT followed by either ipilimumab or placebo.While the primary endpoint of OS was not improved, reductions in PSA and an improvement in progression-free survival were noted. 64The use of radiopharmaceuticals in combination with targeted immunotherapy has also been studied, and a retrospective analysis of over 300 men with mCRPCa receiving radium-223 confirmed improved survival for Black men. 65Nevertheless, further studies exploring the effects of combining immunotherapy and SBRT across different racial groups are urgently needed.

| Bladder cancer
As mentioned above, PM BCa initiatives have targeted actionable mutations in several genes, including TP53, PIK3CA, CDKN1A, ERBB 2 and FGFR. 66This has led to therapeutic tools with promise, but in reality, there is a paucity of study across different racial groups.

| FGFR targeting agents
For example, FGFR has been the focus of several studies with numerous putative targeted agents 67 and although the results of a phase II trial with 90 patients showed response rates of nearly 70% to an agent targeting FGFR2 and FGFR3, the ethnicity of patients in the cohort was not published. 68More recently, maintenance therapy with Avelumab has been shown to lead to a statistically significant improvement in OS over best supportive care in patients with unresectable or metastatic BCa who did not progress after first-line chemotherapy. 71Neither of these important studies published racial demographics in their findings further supporting the sentiment that racially diverse PM research to offset racial inequities is underrepresented.

| Renal cancer
The situation is somewhat different for RCC, where research has yielded useful insights for AA men, although NA and HA populations remain underrepresented.

| Checkpoint inhibitors
In addition to the tyrosine kinase inhibitors targeting VEGF pathways, studies have shown that a combination of targeted therapeutics plus immunotherapy agents can nearly double the survival of patients with RCC. 72These findings were confirmed when Checkmate 025 and 214 helped cement the role of ICIs in the management of RCC. 73,74is is a particularly important finding in the treatment of AA patients, because, as has been discussed, they are less likely to have VHL mutations thus rendering agents that act on the VEGF pathway less effective.

| Abscopal effect
Knowing that certain systemic treatments may not be as effective in AA patients makes exploring the possible role of SBRT more significant.Current studies investigating the role of SBRT in RCC suggest that exploiting the abscopal effect in combination with immunotherapy may improve efficacy for oligometastatic disease in combination with VEGF targeting agents. 75Once again, more study is required.

| CONCLUSION
In the realm of GU cancers, both SDOH and cytogenetic factors play a pivotal role in determining patient outcomes.Unfortunately, AA, HA and NA patients have suffered from a lack of access to quality healthcare, in part due to socioeconomic factors such as lower rates of health insurance, racial biases and geography. 76Adding to this issue is their historical underrepresentation in clinical trials, despite the Food and Drug Administration's attempts to diversify enrollment. 77vertheless, as our understanding of differences in how social, biological and genetic factors influence treatment responses in racially diverse groups improves, clinicians have increasingly been able to direct novel treatments to these populations in an efficacious manner, narrowing the gap in outcomes between AA patients and other races.
As PM becomes increasingly incorporated into treatment planning in the future, underrepresented populations must also be included in all research efforts.PM can be a valuable tool in narrowing the gap in outcomes across ethnic groups.Although further studies are needed, by promoting minority enrollment in trials we will be able to further substantiate the role of PM in this setting.

10
2.1.4| Clinical trial recruitmentPatients from minority backgrounds are underrepresented in PCa clinical trials.11,12An analysis of enrollment in clinical trials leading to F I G U R E 1 Illustrating factors influencing oncological outcomes in ethnic minorities, and the potential benefit of a precision medicine approach (African American [AA], Hispanic American [HA], Native American [NA], social determinants of health [SDOH]).
Molecular tumour profiling and the identification of targetable mutations are a prime focus for PM PCa research, and there are, for example, several androgen receptor pathway inhibitors available that have traditionally been mainstays of treatment.
53reover, some data suggest that AA patients with PCa may respond better to Sipuleucel-T than CAs.A registry study of PSA-matched patients receiving Sipuleucel-T found an OS of 35.3 months for AAs versus 25.8 months for CAs.53TA B L E 1 (Continued) Clinical trials in Black men with metastatic prostate cancer. 69 T A B L E 2 (Continued)Similarly in KEYNOTE-052, first-line pembrolizumab in cisplatinineligible patients with locally advanced or metastatic BCa can lead to a durable clinical response and a prolonged OS.